PET-CRA: Imaging the Neurobiology of a Behavioral Treatment for Cocaine Dependence

• Sponsor: New York State Psychiatric Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00376558
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 50
• Location: 1
• Arms: 2
• Duration (Months): 54
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether patients with the greatest loss of dopamine transmission due to cocaine dependence at pre-treatment PET and MRI scans will be those who fail to respond to substance abuse treatment. This study will also determine whether patients who do respond to treatment will experience a recovery of dopamine function. This study includes free brain imaging and behavioral intervention. Compensation provided for the brain scans.

Condition or Disease	Intervention/Treatment	Phase
Cocaine Dependence	Behavioral: Community Reinforcement Approach	N/A

Detailed Description

Previous studies have shown that cocaine dependence is associated with a decrease in dopamine release in response to a psychostimulant challenge. We have recently completed a study demonstrating that this loss of pre-synaptic dopamine function is associated with the choice to self-administer cocaine in the presence of an alternative reinforcer. This finding consistent with animal models of reinforcement and which show that dopamine transmission serves to modulate reward based behavior, and in this case, allows for a more adaptive response to be made in the presence of a competing reinforcer.

The previous study was performed in non-treatment seeking cocaine dependent subjects using an inpatient laboratory model to measure the choice for cocaine. Thus, the goal of the present proposal is to investigate this association in a more realistic setting where cocaine dependent out patients face the choice between using cocaine and the alternative reinforcers presented to them in a therapeutic setting. The Community Reinforcement Approach with voucher incentives is a treatment for cocaine dependence that has been shown success in a number of controlled studies. Since the basis of this therapy is to reduce the reinforcing value of cocaine by increasing the density of alternative, healthy reinforcers, we have chosen to correlate outcome from this treatment with measures of presynaptic dopamine function. We propose to scan cocaine dependent patients with [11C]raclopride and oral methylphenidate in order to measure dopamine release. Patients will be scanned before treatment and at 12 weeks into therapy. We predict that the patients with the greatest loss of dopamine transmission at the pre-treatment scan will be those who fail to respond to treatment. Furthermore, we hypothesize that the patients who do respond to treatment will experience a recovery of dopamine function, measured at the post-treatment scan.

In addition, subjects enrolled in this study will undergo functional Magnetic Resonance Imaging (fMRI) and spectroscopy studies in order to asses differences in neuronal integrity, learning, and impulse control.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Imaging the Neurobiology of a Behavioral Treatment for Cocaine Dependence
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Contingency Management w/ CRA Cocaine users: Contingency management w/ Community Reinforcement Approach	Behavioral: Community Reinforcement Approach; Community Reinforcement Approach (CRA): The community reinforcement treatment program will be carried out in accordance with NIDA's therapy manual (13).During weeks 13 through 24, patients will meet once per week with their therapists. Sessions will focus on promoting continued change in the life areas addressed in the first 12 weeks of treatment or new components are added as needed.
No Intervention: Healthy Control A group of healthy matched comparison subjects with no DSM-IV axis I Disorder was included; they were matched for cigarette smoking, gender, and ethnicity.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Binding Potential of [11C]Raclopride [baseline and 3 months]

   The relationship between Methylphenidate-induced Dopamine Release in the Striatum (Measured by Displacement of [11C]-Raclopride by Oral Methylphenidate) and Treatment Response (Measured Using Community Reinforcement Approach and Contingency Management) was studied. Dopamine Function was assessed by evaluation of endogenous Dopamine release over the course of treatment (i.e., at 3 months as compared to baseline). Endogenous Dopamine release is inversely related to the change in binding potential (delta BPND) of [11C]raclopride, in that a negative delta BPND, or increased displacement of [11C]raclopride, reflects an increase in the release of endogenous dopamine over the course of treatment.

Secondary Outcome Measures

1. Cocaine Craving, Withdrawal Symptoms, Pattern of Cocaine Use [2x/week for 24 weeks]

   measurement of abstinence, measured as vouchers earned and clinical appointments attended using CRA

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Males or females between 21 and 45 years old

• Fulfill DSMIV criteria for cocaine abuse or dependence

• Able to give informed consent and comply with study procedures

• Medically Healthy

Exclusion Criteria:

• Major DSM-IV Axis I disorder other than cocaine abuse or dependence. Subjects with a history of other psychostimulant abuse/dependence or compulsive gambling will be excluded.

• Current use of opiates, sedative-hypnotic, and/or cannabis more than twice a week (use less than twice a week is acceptable).

• Current use of psychotropic medication such as antipsychotics or antidepressants.

• Presence or positive history of severe medical or neurological illness (including epilepsy), or any cardiovascular disease, low hemoglobin (Hb < 14 gm/dL in males, Hb < 12 gm/dL in females), or SGOT or SGPT > 2-3 times normal. Chronic active hepatitis B or C will also be an exclusion criteria.

• Resting SBP >150, DBP > 90

• Pregnancy or lactation, lack of effective birth control during 15 days before the scans*

• Evidence /report of any heart abnormality during intake medical history, EKG or physical exam.

• Metal implants or paramagnetic objects contained within the body which may interfere with the MRI scan, as determined in consultation with a neuroradiologist and according to the guidelines set forth in the following reference book commonly used by neuroradiologists: "Guide to MR procedures and metallic objects" Shellock, PhD, Lippincott Williams and Wilkins, NY 2001.

• Lifetime exposure to radiation in the workplace, or history of participation in nuclear medicine procedures, including research protocols **

• Positive Allen Test indicating lack of collateral blood flow to hand

• History of sensitivity to methylphenidate

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York State Psychiatric Institute	New York	New York	United States	10032

Sponsors and Collaborators

• New York State Psychiatric Institute
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Diana Martinez, MD, Research Foundation for Mental Hygiene, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• Responsible Party: New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT00376558
• Other Study ID Numbers: #5158; R01DA020855-02
• First Posted: Sep 15, 2006
• Last Update Posted: Jul 1, 2016
• Last Verified: May 1, 2016

• Keywords provided by New York State Psychiatric Institute: cocaine dependence
• Additional relevant MeSH terms: Cocaine-Related Disorders

Study Results

Participant Flow

Arm/Group Title	Cocaine Users	Control Subjects
Arm/Group Description	Cocaine users receiving CRA	Healthy controls who undergo scans
Period Title: Overall Study
STARTED	25	25
COMPLETED	25	25
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Cocaine Users	Control Subjects	Total
Arm/Group Description	Cocaine users receiving CRA	Healthy controls who undergo scans	Total of all reporting groups
Overall Participants	25	25	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	25 100%	25 100%	50 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37 (7)	38 (6)	37 (7)
Sex: Female, Male (Count of Participants)
Female	3 12%	3 12%	6 12%
Male	22 88%	22 88%	44 88%
Region of Enrollment (participants) [Number]
United States	25 100%	25 100%	50 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Binding Potential of [11C]Raclopride
Description	The relationship between Methylphenidate-induced Dopamine Release in the Striatum (Measured by Displacement of [11C]-Raclopride by Oral Methylphenidate) and Treatment Response (Measured Using Community Reinforcement Approach and Contingency Management) was studied. Dopamine Function was assessed by evaluation of endogenous Dopamine release over the course of treatment (i.e., at 3 months as compared to baseline). Endogenous Dopamine release is inversely related to the change in binding potential (delta BPND) of [11C]raclopride, in that a negative delta BPND, or increased displacement of [11C]raclopride, reflects an increase in the release of endogenous dopamine over the course of treatment.
Time Frame	baseline and 3 months

Outcome Measure Data

Analysis Population Description

Analysis for change in binding potential (binding potential difference; at baseline versus stimulant induced binding potential) was done with 24 cocaine users since one of the subjects only underwent baseline scanning. However, treatment data for all 25 cocaine users was used.

Arm/Group Title	Cocaine Users	Control Subjects
Arm/Group Description	Cocaine users receiving CRA	Healthy controls who undergo scans
Measure Participants	24	25
Mean (Standard Deviation) [ratio]	-13.7 (8.7)	-5.8 (8.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cocaine Users, Control Subjects
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Cocaine Craving, Withdrawal Symptoms, Pattern of Cocaine Use
Description	measurement of abstinence, measured as vouchers earned and clinical appointments attended using CRA
Time Frame	2x/week for 24 weeks

Outcome Measure Data

Analysis Population Description

The number of subjects was determined from previous studies using CM/CRA

Arm/Group Title	Cocaine Abuser Undergoing CM With CRA Treatment
Arm/Group Description	Participants receive voucher points for each urine sample that tested negative for benzoylecgonine. Failure to submit a scheduled sample was treated as cocaine +. Voucher points have a monetary value that can be redeemed for goods/services that are approved by the therapist. Points ($0.25) were acquired on an escalating schedule that started at 10 points for the 1st cocaine-free sample, and each subsequent cocaine-free sample increased the value by 5 points. A bonus of 40 points ($10.00) for every 3 consecutive negative sample. Abstinence was confirmed by onsite urine test (Abuscreen On-Trak system, Roche Diagnostics). Missed clinic visits and urine samples that are considered + reset the points to the initial $2.50 value and the escalation schedule resume. Submission of 5 consecutive - samples after a + urine returns the voucher points to the value prior to reset. Points earned are never lost. A maximum of $997.50 is earned for submitting negative samples at all treatment visits.
Measure Participants	25
Mean (Standard Deviation) [dollars]	650 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cocaine Users
	Comments	The limbic striatum was our primary region of interest using an unpaired t test to compare BPND and deltaBPND between the treatment responders and non-responders.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	delta bpnd
	Estimated Value	-12
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Deviation; Value: 7
	Estimation Comments

Adverse Events

Arm/Group Title	Cocaine Users		Control Subjects
Arm/Group Description	Cocaine users receiving CRA		Healthy controls who undergo scans
All Cause Mortality
	Cocaine Users		Control Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cocaine Users		Control Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Cocaine Users		Control Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.